Clinical trials are research studies carried out in human participants to evaluate medical interventions. Clinical trials are conducted when there is significant evidence suggesting a new treatment will improve the care of patients with a particular disease. Before a clinical trial is conducted, tests and experiments are conducted to assess the treatment. This is called preclinical research. This research is not performed in humans. All drugs go through preclinical research to gain insight before human trials. After preclinical research shows that a treatment is relatively safe and shows evidence it may be effective, clinical trials are conducted. Clinical trials are used to ensure the treatment works and is safe for human use. Trials are broken down into phases allowing different information to be attained (1). Phase I: Phase I aims to determine the optimal dose of a medicine with the least amount of side effects. At this stage, the trial group is small (15-30 patients). Low doses of a medication are given and slowly increased throughout the trial until the side effects become intolerable or the desired outcome is observed. The goal of Phase I is to assess the safety and tolerability of a drug. It is not yet known if the drug will be effective or not. Once the drug is demonstrated to be safe, it moves on to Phase II.
Phase II: Phase II trials continue to assess the safety of a drug while starting to measure the effectiveness. The trial group in this phase is a bit larger. Once the drug has shown that it works in this preliminary group and continues to be safe, it moves on to Phase III.
Phase III: Majority of drugs that will fail, fail in this phase (2). Phase III aims to compare the new medication to the standard of care treatment (if available) and are conducted in a large population of 100 or more participants. These studies compare the side effects and whether the new medication is as effective as prior ones. Patients participating are randomly put into treatment groups and given either the standard of care or the new drug of interest. Neither the doctors or the patients know what group they are in. Since TGCT has no current standard of care, Phase III trials are done with a placebo group. This means that patients are either given the medication of interest or a sugar pill. Neither the doctors nor the patients know what group they are in. Oftentimes, patients in the placebo group are allowed to switch into the treatment group or the identity of the groups is revealed after a certain amount of time has gone by. At any phase, the trial will be stopped if side effects become too severe. In order for the FDA to approve a treatment for the general public, Phase III trials are often required. For TGCT, due to it being an orphan disease with no pharmacological treatment options until Pexidartinib was approved in 2019, there are ongoing trials to improve the tolerability profile and effectiveness of these CSF1 inhibitors.
Current Clinical Trials for TGCT
DCC-3014, Vimseltinib (Deciphera) is the name of a medication currently in trial for TGCT. It is a Phase II/III study, meaning the side effects are being evaluated as well as the effectiveness of the drug. The Phase III trial is known as MOTION. Preliminary data shows it has an improved tolerability profile and remains effective at shrinking the tumor. It is currently recruiting at 18 different global clinical locations. For more information on the trial and the locations, visit the Phase II clinical trial website for DCC-3014, Phase III clinical trial website for Vimseltinib or ask your healthcare provider. To learn more, check out Deciphera's Vimseltinib page.
Cabiralizumab (FPA008, Five Prime Therapeutics) recently completed Phase I/II trials to evaluate the safety, tolerability, and effectiveness of Cabiralizumab in diffuse TGCT. While both DCC-3014 and Pexidartinib are molecule-based drugs (like many oral pills on market), this drug relies on a protein antibody that blocks CSF1 by holding onto it and preventing it from reaching TGCT and surrounding cells. By blocking CSF1, the tumor cannot grow and develop. This clinical trial took place at 12 different global clinical locations. For more information, visit the clinical trial website for Cabiralizumab or ask your healthcare provider. As of 2021, Amgen has acquired this company. It is unknown whether this drug will continue.
AMB-05X (AmMax Bio, Inc.) is recruiting for a Phase I/II clinical trial on a monoclonal antibody local injection for the treatment of TGCT of the knee. In the Phase II expansion trial, other disease locations such as the ankle and hip will be included. This trial intends to evaluate the effectiveness safety, toxicity, and tolerability of AMB-05X as a 12 week treatment. AMB-05X is administered as a joint injection to the knee for 12 weeks (1 injection every 2 weeks, 6 injections total). AMB-05X uses a monoclonal antibody that is designed to target CSF1 and block it from signaling to TGCT and surrounding cells. For more information, visit the clinical trial website for AMB-05X or ask your healthcare provider.
Lastly, trials are in place to evaluate discontinuation and re-treatment with the currently approved Pexidartinib. These trials are in place to set a guideline for treatment duration and discontinuation post FDA-approval. This trial is being conducted at 15 different global clinical sites. For more information, visit the clinical trial website for Pexidartinib or ask your healthcare provider.
Emactuzumab (SynOx Therapeutics) is an intravenous monoclonal antibody that was previously tested in a Phase I trial. A Phase II trial has been started in select countries. This trial is currently under review.
1. Phases of clinical trials. NCCN Guidelines for Patients. https://www.nccn.org/patients/resources/clinical_trials/phases.aspx. Published 2021. 2. Fogel DB. Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemp Clin Trials Commun. 2018. doi:10.1016/j.conctc.2018.08.001